RET Fusion-positive Non-small Cell Lung Cancer Research Articles

Abstract 5833: Genomic mechanisms of RET inhibitor resistance in RET-fusion positive NSCLC

Abstract RET fusions are a driver oncogene detected in 1-2% of non-small cell lung cancer (NSCLC) cases. Currently, two selective RET inhibitors (RETi), selpercatinib and pralsetinib have received FDA approval for RET fusion-positive NSCLC. However, RET fusions are highly heterogeneous and the impact of specific fusion partners and breakpoints on RETi sensitivity is not well understood. Moreover, most patients eventually develop resistance to RETi, and secondary RET mutations are thought to be a key mechanism of acquired resistance. Thus, we aimed to identify RET-dependent mechanism of RETi resistance in effort to improve treatment options and clinical outcomes. We engineered a panel of Ba/F3 cells expressing various RET fusion partners and breakpoints observed in clinical cases of NSCLC and evaluated their drug sensitivity profile against a panel of RETi including selpercatinib, pralsetinib, TPX-0046, lovatinib, zeteletinib and ponatinib. We determined that individual RET fusions impart distinct sensitivities to RETi. For example, cells expressing KIF-RET (K22, R12) were sensitive to selpercatinib and pralsetinib but less sensitive to ponatinib, whereas cells expressing KIF-RET (K15, R12) were highly sensitive to selpercatinib, pralsetinib, and ponatinib. Moreover, using RET-fusion positive NSCLCs, we observed that the RETi sensitivity profile of human cell lines was similar to that observed using Ba/F3 models. To identify potential resistance mutations, we utilized the LentiMutate approach. In KIF5B-RET (K15, R12) expressing cells, we identified G810S as being associated with resistance to both selpercatinib and pralsetinib, a finding consistent with previous reports and clinical observations. In addition, we identified Y806H/N, V804M/E, and M918T as being associtated with selpercatinib-resistance and L730I/V, E732K, and Y806H/N as being associated with pralsetinib-resistance. We next constructed Ba/F3 cells expressing KIF5B-RET in combination with each secondary mutation and evaluated RETi sensitivity. G810S and Y806N conferred resistance to selpercatinib and pralsetinib, as well as to RET-targeting multi-kinase inhibitors. V804M/E mutations conferred resistance to selpercatinib but not pralsetinib, whereas L730I/V and E732K mutations conferred resistance to pralsetinib but not selpercatinib, demonstrating RETi-specific resistance mutations. Cells expressing G810S secondary mutations were resistant to selpercatinib and pralsetinib, but sensitive to zeteletinib. Collectively, we show that individual RET fusion variants have distinct drug sensitivity profiles and that secondary resistance mutations are non-overlapping between RETi. The comprehensive characterization of RET-dependent mechanisms of resistance to RETi may provide therapeutic guidance for treating RET-fusion driven NSCLC and provide structural insights that can guide the development of new therapeutic regimens. Citation Format: Ximeng Liu, Monique Nilsson, Tomohiro Takehara, Junqin He, Xiaofang Huo, Ashwani Kumar, John Heymach, Ralf Kittler. Genomic mechanisms of RET inhibitor resistance in RET-fusion positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5833.

Abstract 1958: EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs

Abstract RET fusions are an oncogenic driver mutation occurring in 1-2% non-small cell lung cancer (NSCLC). Currently, RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved for this patient population, demonstrating favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC. However, tumors eventually become refractory to selective RET inhibitor monotherapy. We sought to identify signaling pathways which mediate RET-independent acquired resistance to RET inhibitors and effective therapeutic combinations to overcome resistance. Using LC-2/ad (CCDC6-RET) NSCLC cells, we assessed the expression and activation of critical signaling pathways at a proteomic level following RET knockdown using reverse-phase protein array. RET knockdown resulted in rapidly increased adaptive upregulation of EGFR, HER2, MET, mTOR and MEK pathway signaling; observations were confirmed by Western Blotting. To determine whether EGFR or MET signaling facilitate RET inhibitor resistance, LC-2/ad and NCCE-TH1101 (KIF5B-RET) NSCLC cells were treated with increasing concentrations of selpercatinib or pralsetinib with or without ligands for these receptors, EGF or HGF respectively, and after five days cell viability was measured by CellTiter Glo. EGFR and MET signaling promoted RET TKI resistance in both cell lines. Next, to evaluate whether blockade of EGFR or MET signaling could enhance the activity of RET inhibitors, we treated LC-2/ad and NCCE-TH1101 cells with RET TKIs alone or in combination with the EGFR TKI erlotinib or poziotinib, or the MET inhibitor SU11274. We observed an additive effect with EGFR but not MET inhibitors when combined with RET TKIs. Western blot analysis revealed that EGFR signaling could reactivate mTOR and MAPK signaling after RET TKI treatment. Therefore, we next tested whether inhibition of these downstream pathways might enhance RET TKI sensitivity. We observed that treatment of LC-2/ad and NCCE-TH1101 cells with an mTOR inhibitor (everolimus) or a MEK inhibitor (trametinib) in combination with RET TKIs increased the anti-tumor activity or RET inhibitors. Finally, we established cells with acquired resistance to selpercatinib and pralsetinib. RET TKI resistant cells did not harbor secondary RET fusion mutations but underwent epithelial to mesenchymal transition and exhibited pan-RET inhibitor resistance. Moreover, RET TKI resistant cells showed increased cell surface expression of EGFR and MET by flow cytometry. RET TKI resistant cells were sensitive to mTOR or MEK inhibitors in combination with RET TKIs. Collectively, our findings indicate that in RET-fusion positive NSCLC tumor cells, activation of bypass pathways including the EGFR, MAPK, mTOR pathways may facilitate RET inhibitor resistance and that blockade of bypass pathways may enhance the efficacy of selective RET inhibitors and overcome acquired RET TKI resistance. Citation Format: Tomohiro Takehara, Monique B. Nilsson, Ximeng Liu, Hibiki Udagawa, Naoto Morikawa, Alissa Poteete, Junqin He, Xiaoxing Yu, Thiru Arumugam, Koichi Goto, John V. Heymach. EGFR and mTOR signaling facilitate RET-independent resistance to selective RET-TKIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1958.

Abstract 4998: Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation

Abstract Background: Oncogenic alteration in RET, representing 1-2% of non-small cell lung cancer (NSCLC), is one of the important targets. Pralsetinib is a selective RET inhibitor that targets RET fusions. We present a case series on opportunistic infections and the mechanism of immunosuppression. Methods: From October 2021 to March 2022, we administered pralsetinib to a total of 15 patients with NSCLC harboring RET fusion. We retrospectively analyzed the clinical efficacy and adverse event related to pralsetinib. To investigate the potential impact of pralsetinib on T-cells, we examined cytokine release from Jurkat T (JT) cells after pralsetinib treatment. To test if Stat5 bind to IL-2 promotor, we conducted Chromatin Immunoprecipitation (ChIP). Results: Out of a total of 18 patients with measurable disease, 14 patients (93%) achieved a partial response. With the median follow-up duration of 8.7 months, four cases of opportunistic infections were occurred. Notably, three patients (16.6%) experienced invasive pulmonary aspergillosis, and one patient (5.5%) experienced cytomegalovirus pneumonia. To mimic conditions akin to activated T cells, we treated JT cells with PMA and ionomycin, inducing IL-2 release through the binding of NFAT, AP-1, and NF-κB to the IL-2 promoter. Following approximately two weeks of pralsetinib treatment, a decrease of IL-2 releases, the inhibition of Jak3 and the reduced-expression of JunB and c-Jun was observed. Additionally, to investigate the direct correlation between Jak3 and IL-2 release, JT cells were treated with ritlecitinib, the Jak3-selective inhibitor, for approximately two weeks. Like pralsetinib, a reduction in IL-2 release was observed. Furthermore, based on the evidence that Stat5 inhibition leads to reduced IL-2 release, we also showed that the transcription factor Stat5, a direct downstream signaling component of Jak3, binds to the IL-2 promoter during the activation of Jurkat T cells. Conclusion: Pralsetinib inhibits additional IL-2 production by blocking Jak3/Stat5 activation triggered by IL-2 released during early T cell activation. As a result, the Jak3 inhibition induced by pralsetinib leads to a decrease in JunB/c-Jun expression and blocking Stat5 activation by reducing IL-2 release. Consequently, Pralsetinib-related opportunistic infections may be caused by inhibition of the JAK3 pathway and IL-2 release. Citation Format: Shinkyo Yoon, Hyun-Min Ryu, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4998.

Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data

BackgroundThe impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood.MethodsWe screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).ResultsA total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4–7.6 months) and the median OS was 19 months (95% CI: 9.7–28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not.ConclusionsPatients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

[Chinese expert consensus on the diagnosis and treatment of advanced RET fusion-positive non-small cell lung cancer (2023 edition)].

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.

Pralsetinib-associated pneumonia in RET fusion-positive non-small cell lung cancer

ObjectiveOncogenic alternation in RET is one of the important targets of non-small cell lung cancer (NSCLC). Pralsetinib has shown great efficacy in RET fusion-positive NSCLC, but a series of adverse reactions will inevitably occur in the meantime. We aimed to explore the clinical characteristics of patients with pneumonia and recognition it in early stage, so patients could longer benefit from pralsetinib.MethodsThis is a multicenter, retrospective study. RET fusion-positive advanced NSCLC patients who developed pneumonia during pralsetinib treatment from January 2020 to December 2022 were included. Clinical data, time to onset of pneumonia, methods of pneumonia diagnosis, treatment with pneumonia, prognosis of pneumonia, and the effect of pneumonia on the efficacy of pralsetinib.ResultsA total of 8 patients with pneumonia were included in the study, most of which were non-smoking female patients and the main fusion gene was KIF5B (87.5%), which was consistent with the general characteristics of RET fusion population. The median occurrence time of pralsetinib-associated pneumonia was 2.15 (range 1.1–6.63) months. All patients were infected by opportunistic pathogens, and the most common pathogen was human herpesviruses and pneumospora yerbii. Fever was always the first symptom, and timely anti-infective treatment including antibiotics, antiviral drugs, and antifungal drugs was effective. Until February 28, 2023, the median follow-up time was 18.7 months, the mean PFS of patients was 17.4 months, and the median PFS was not reached. Fortunately, patients who restarted pralsetinib after infection control continued to benefit.ConclusionsOpportunistic infection may be a unique adverse effect of pralsetinib. During the treatment of pralsetinib, we should be vigilant about the occurrence of pneumonia and achieve early recognition and timely treatment.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7months (95% CI, 8.7-not estimable) in pretreated patients and 12.7months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. NCT03037385.

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .

Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer

Objective: To investigate the clinicopathological features, treatment and prognosis of patients with RET fusion positive non-small cell lung cancer (NSCLC). Methods: A total of 1 089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020. In all cases, multiple gene fusion detection kits (fluorescent PCR method) were used to detect the gene status of RET, EGFR, ALK, ROS1, KRAS, BRAF and HER2; and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins. The correlation between RET-fusion and patients' age, gender, smoking history, tumor stage, grade, pathologic type, and PD-L1, mismatch repair related protein expression was analyzed. Results: There were 22 cases (2.02%) detected with RET fusion-positive in 1 089 NSCLC patients, in which 11 males and 11 females; and the median age was 63.5 years. There were 20 adenocarcinomas, including 11 acinar predominant adenocarcinoma (APA), five solid predominant adenocarcinoma (SPA) and four lepidic predominant adenocarcinoma (LPA); There were one case each of squamous cell carcinoma (non-keratinizing type) and sarcomatoid carcinoma (pleomorphic carcinoma). There were 6 and 16 patients with RET fusion-positive who were in stage Ⅰ-Ⅱ and Ⅲ-Ⅳ respectively, and 16 cases with lymph node metastasis, 11 cases with distant metastasis. Among RET fusion-positive cases, one was detected with HER2 co-mutation. The tumor proportion score of PD-L1≥1% in patients with RET fusion positive lung cancer was 54.5% (12/22). Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC. Four patients with RET fusions positive (two cases of APA and two cases of SPA) received pratinib-targeted therapy, and two showed benefits from this targeted therapy. Conclusions: The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA. RET fusion-positive NSCLC patients are associated with advanced clinical stage, lymph node metastases, and they may benefit from targeted therapy with RET-specific inhibitors.

Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n= 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

LIBRETTO-432, a phase III study of adjuvant selpercatinib or placebo in stage IB-IIIA RET fusion-positive non-small-cell lung cancer.

Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system.

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes

PurposeRearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown.MethodsData from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs).ResultsPatients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation.ConclusionSelective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

AcceleRET Lung: A phase 3 study of first-line pralsetinib in patients with RET fusion–positive advanced/metastatic NSCLC.

TPS9159 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). Pralsetinib is a potent, selective RET inhibitor, approved in the US and EU for the treatment of metastatic RET fusion–positive NSCLC based on the phase 1/2 ARROW study (NCT03037385). In the ARROW study (data cutoff: Nov 6, 2020), patients who initiated 400 mg once daily (QD) of pralsetinib after platinum-based chemotherapy achieved an overall response rate (ORR) of 62%, per independent central review. In the treatment-naïve group, the ORR was 79%. Most treatment-related adverse events were grade 1–2 across the entire safety population treated at 400 mg QD (n=471). AcceleRET Lung, an international, open-label, randomized, phase 3 study (NCT04222972), will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion–positive NSCLC. Abstracts for this study were previously submitted to the European Lung Cancer Congress 2020, the American Society of Clinical Oncology 2020 annual meeting, and 2020 World Conference on Lung Cancer. Methods: Approximately 226 patients with metastatic RET fusion–positive NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab [at investigator’s discretion]; squamous histology: platinum/gemcitabine or platinum + pembrolizumab + paclitaxel/nab-paclitaxel followed by maintenance pembrolizumab). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET fusion–positive tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients with central nervous system metastases were permitted if asymptomatic and on a stable dose of corticosteroids. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance was an exploratory endpoint. Recruitment has begun with sites (active or planned) in North America, Central America, Europe and Asia. Clinical trial information: NCT04222972.

Pralsetinib: A Review in Advanced RET Fusion-Positive NSCLC.

Activating mutations in the proto-oncogene RET have been identified as an oncogenic driver of non-small cell lung cancer (NSCLC) in a small subset of patients. Pralsetinib (Gavreto®) is an orally-administered, next-generation, small-molecule selective RET inhibitor that is approved for the treatment of RET fusion-positive metastatic NSCLC. In the pivotal phase I/II ARROW trial, pralsetinib demonstrated rapid and durable anti-tumour activity in patients with advanced RET fusion-positive NSCLC who were previously treated with platinum-based chemotherapy or were treatment-naïve. Pralsetinib also showed clinical activity against intracranial metastases arising from NSCLC. Pralsetinib had a manageable tolerability profile, with the most common grade 3 treatment-related adverse events being neutropenia, hypertension, anaemia and decreased white blood cell count. Currently available data indicate that pralsetinib is a promising new targeted treatment option for patients with advanced RET fusion-positive NSCLC.

Molecular Testing and Treatment Strategies in RET-Rearranged NSCLC Patients: Stay on Target to Look Forward

RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as pralsetinib and selepercatinib, demonstrated high efficacy and favorable tolerability in advanced RET-rearranged NSCLC patients, leading to their introduction in the clinical setting. Among the different approaches available for the identification of RET rearrangements, next-generation sequencing (NGS) assays present substantial advantages in terms of turnaround time and diagnostic accuracy, even if potentially limited by accessibility issues. The recent advent of novel effective targeted therapies raises several questions regarding the emergence of resistance mechanisms and the potential ways to prevent/overcome them. In this review, we discuss molecular testing and treatment strategies to manage RET fusion positive NSCLC patients with a focus on resistance mechanisms and future perspectives in this rapidly evolving scenario.

Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase II clinical trial (LIBRETTO-321).

Introduction:Oncogenic alterations in RET occur in 1–2% of non-small-cell lung cancers (NSCLCs). The efficacy and safety of the first-in-class, highly selective, and potent RET inhibitor selpercatinib in Chinese patients with RET fusion-positive NSCLC remains unknown.Methods:In this open-label, multicenter, phase II study (NCT04280081), patients with advanced RET-altered solid tumors received selpercatinib (160 mg orally twice daily) in a 28-day cycle. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints included duration of response, central nervous system (CNS) response, and safety. Efficacy against NSCLC was assessed in the primary analysis set (PAS; centrally confirmed RET status) and in all enrolled patients with NSCLC.Results:Of 77 enrolled patients, 47 had RET fusion-positive NSCLC. After 9.7 months of median follow-up, IRC-assessed ORR in the PAS (n = 26) was 69.2% [95% confidence interval (CI), 48.2–85.7] and 94.4% of responses were ongoing; the ORR was 87.5% and 61.1% in treatment-naïve and pre-treated patients, respectively. IRC-assessed ORR in all patients with NSCLC (n = 47) was 66.0% (95% CI, 50.7–79.1). Among five patients with measurable CNS metastases at baseline, four (80%) achieved an IRC-assessed intracranial response. In the safety population (n = 77), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common grade ⩾3 TEAE was hypertension (19.5%). Three (3.9%) patients discontinued therapy due to treatment-related AEs; no deaths occurred due to treatment-related AEs.Conclusion:Selpercatinib, with potent and durable antitumor activity including intracranial activity, was well tolerated in Chinese patients with RET fusion-positive NSCLC, consistent with LIBRETTO-001 (ClinicalTrials.gov: NCT04280081).

Pralsetinib: Treatment of metastatic RET fusion-positive non-small cell lung cancer.

To review the pharmacology, efficacy, safety, dosing and administration, and place in therapy of pralsetinib, a tyrosine kinase inhibitor, for the treatment of metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). RET fusion-positive NSCLC is a rare cancer caused by chromosomal rearrangements that lead to fusions of the RET gene with other genes, such as KIF5B and CCDC6. Until recently, patients were treated with platinum-based chemotherapy or multitargeted tyrosine kinase inhibitors. However, because of their nonspecific mechanism of action, these drugs did not have high response rates. In September 2020, the Food and Drug Administration approved pralsetinib, the first once-daily oral tyrosine kinase inhibitor, for patients with metastatic RET fusion-positive NSCLC. Pralsetinib has been demonstrated to have response rates of 57% and 70% in patients who were previously treated with platinum chemotherapy and patients who were treatment naive, respectively. Clinicians using pralsetinib should monitor for fatigue, hepatotoxicity, hemorrhagic events, hypertension, myelosuppression, pyrexia, and respiratory infections, as these may require treatment interruption, dose reduction, or treatment discontinuation. Pralsetinib is a unique targeted tyrosine kinase inhibitor approved for the treatment of patients with RET fusion-positive metastatic NSCLC who may desire a once-daily regimen.

RET Inhibitors in Non-Small-Cell Lung Cancer.

Simple SummaryNon-small cell lung cancer (NSCLC) remains a significant cause of death worldwide, despite the significant progresses to date. Multiple molecular alterations have been identified in NSCLC, leading to the development of target-based agents that have shown significant clinical benefits. Rearranged during Transfection (RET) fusions have recently emerged as a new potential target and a number of non-selective and selective RET inhibitors have been tested in RET positive NSCLC. In this review we analyse and summarise the characteristics of RET functions and its alterations in NSCLC. We then present the state of the art RET inhibitors in the treatment of NSCLC, discussing the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients.RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer.

Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1-2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy. As with use of TKIs in other oncogene-addicted NSCLCs, development of acquired resistance is pervasive and should be specifically delineated through use of repeat tissue biopsy with genetic profiling at the time of disease progression. If an actionable resistance mechanism emerges for which there is a candidate targeted therapy, combination inhibition should be considered. Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects. Single-agent immunotherapy has minimal activity in RET fusion-positive NSCLC. The role of combination chemotherapy and immunotherapy requires further study but may be considered, particularly in the presence of an activating KRAS alteration. While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.

US Food and Drug Administration regulatory updates in neuro-oncology.

ObjectiveContemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year.MethodsOncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed.ResultsFive oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, “Cancer Clinical Trial Eligibility Criteria: Brain Metastases” and “Evaluating Cancer Drugs in Patients with Central Nervous System Metastases” were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials.ConclusionsDespite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.